TY - JOUR
T1 - Antagonistic regulation of PAF1C and p-TEFb is required for oligodendrocyte differentiation
AU - Kim, Suhyun
AU - Kim, Jun Dae
AU - Chung, Ah Young
AU - Kim, Hyung Seok
AU - Kim, Young Seop
AU - Kim, Myoung Jin
AU - Koun, Soonil
AU - Lee, You Mie
AU - Rhee, Myungchull
AU - Park, Hae Chul
AU - Huh, Tae Lin
PY - 2012/6/13
Y1 - 2012/6/13
N2 - Oligodendrocytes are myelinating glial cells in the CNS and are essential for proper neuronal function. During development, oligodendrocyte progenitor cells (OPCs) are specified from the motor neuron precursor domain of the ventral spinal cord and differentiate into myelinating oligodendrocytes after migration to the white matter of the neural tube. Cell cycle control of OPCs influences the balance between immature OPCs and myelinating oligodendrocytes, but the precise mechanism regulating the differentiation of OPCs into myelinating oligodendrocytes is unclear. To understand the mechanisms underlying oligodendrocyte differentiation, an N-ethyl-Nnitrosourea- based mutagenesis screen was performed and a zebrafish leo1 mutant, dalmuri (dal knu6) was identified in the current study. Leo1 is a component of the evolutionarily conserved RNA polymerase II-associated factor 1 complex (PAF1C), which is a positive regulator of transcription elongation. The dal knu6 mutant embryos specified motor neurons and OPCs normally, and at the appropriate time, but OPCs subsequently failed to differentiate into myelinating oligodendrocytes and were eliminated by apoptosis. A loss-offunction study of cdc73, another member of PAF1C, showed the same phenotype in the CNS, indicating that PAF1C function is required for oligodendrocyte differentiation. Interestingly, inhibition of positive transcription elongation factor b (p-TEFb), rescued downregulated gene expression and impaired oligodendrocyte differentiation in the dal knu6 mutant and Cdc73-deficient embryos. Together, these results indicate that antagonistic regulation of gene expression byPAF1Cand p-TEFb plays a crucial role in oligodendrocyte development in the CNS.
AB - Oligodendrocytes are myelinating glial cells in the CNS and are essential for proper neuronal function. During development, oligodendrocyte progenitor cells (OPCs) are specified from the motor neuron precursor domain of the ventral spinal cord and differentiate into myelinating oligodendrocytes after migration to the white matter of the neural tube. Cell cycle control of OPCs influences the balance between immature OPCs and myelinating oligodendrocytes, but the precise mechanism regulating the differentiation of OPCs into myelinating oligodendrocytes is unclear. To understand the mechanisms underlying oligodendrocyte differentiation, an N-ethyl-Nnitrosourea- based mutagenesis screen was performed and a zebrafish leo1 mutant, dalmuri (dal knu6) was identified in the current study. Leo1 is a component of the evolutionarily conserved RNA polymerase II-associated factor 1 complex (PAF1C), which is a positive regulator of transcription elongation. The dal knu6 mutant embryos specified motor neurons and OPCs normally, and at the appropriate time, but OPCs subsequently failed to differentiate into myelinating oligodendrocytes and were eliminated by apoptosis. A loss-offunction study of cdc73, another member of PAF1C, showed the same phenotype in the CNS, indicating that PAF1C function is required for oligodendrocyte differentiation. Interestingly, inhibition of positive transcription elongation factor b (p-TEFb), rescued downregulated gene expression and impaired oligodendrocyte differentiation in the dal knu6 mutant and Cdc73-deficient embryos. Together, these results indicate that antagonistic regulation of gene expression byPAF1Cand p-TEFb plays a crucial role in oligodendrocyte development in the CNS.
UR - http://www.scopus.com/inward/record.url?scp=84862268845&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.5344-11.2012
DO - 10.1523/JNEUROSCI.5344-11.2012
M3 - Article
C2 - 22699901
AN - SCOPUS:84862268845
SN - 0270-6474
VL - 32
SP - 8201
EP - 8207
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -